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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5192_Библиотеки_им_академика_М_И_Перельмана.pdf
2.3 Corticosteroids
Indications: systemic vasculitis, systemic lupus
erythematosus (SLE), pyoderma gangrenosum, and
bullous pemphigoid
AEs: sudden cardiac death, atrial fbrillation, anaphylaxis,
electrolyte shits, and seizures
Wet wrap therapy—topical steroid covered by a wetted
layer o bandages, ollowed by a dry outside layer →
occludes topical steroid or increased penetration and
absorption
■
Use with high-potency steroids has the potential or
HPA axis suppression
Intralesional CS
Typically triamcinolone acetonide 2 to 40 mg/mL,
depending on disorder/location/thickness o lesion
Used or prurigo nodularis, keloids, alopecia areata,
discoid lupus, and lichen planopilaris
AEs: atrophy (inject in dermis!) and hypopigmentation
Topical CS (Table 2.4)
O note, more potent topical steroids (e.g., clobetasol)
and those in more highly absorbed bases (e.g., gels and
ointments) are more likely to cause adverse cutaneous
eects
■
Potency based o o vasoconstriction assay
■
Risk o HPA suppression is low with topical steroids
■
Can develop contact dermatitis to topical steroids (see
Chapter 3.2)
One fngertip unit 5 0.5 g o topical steroids and covers
2% body surace area
Table 2.4 Potency o Topical Steroids
Class Drug Dosage Form(s) Strength (%)
I. Very high potency Augmented betamethasone
II. High potency Amcinonide Cream, lotion, ointment 0.1
III-IV. Medium potency Betamethasone valerate Cream, oam, lotion, ointment 0.1
V. Lower-medium potency Hydrocortisone butyrate Cream, ointment, solution 0.1
VI. Low potency Alclometasone dipropionate Cream, ointment 0.05
VII. Lowest potency Dexamethasone Cream 0.1
From Eichenfeld LF, Tom WL, Berger TG, et al. Guidelines o care or the management o atopic dermatitis: section 2. Management and treatment o atopic
dermatitis with topical therapies. J Am Acad Dermatol. 2014;71(1):116–132.
dipropionate
Clobetasol propionate Cream, oam, ointment 0.05
Dilorasone diacetate Ointment 0.05
Halobetasol propionate Cream, ointment 0.05
Augmented betamethasone
dipropionate
Betamethasone dipropionate Cream, oam, ointment, solution 0.05
Desoximetasone Cream, ointment 0.25
Desoximetasone Gel 0.05
Dilorasone diacetate Cream 0.05
Fluocinonide Cream, gel, ointment, solution 0.05
Halcinonide Cream, ointment 0.1
Mometasone uroate Ointment 0.1
Triamcinolone acetonide Cream, ointment 0.5
Clocortolone pivalate Cream 0.1
Desoximetasone Cream 0.05
Fluocinolone acetonide Cream, ointment 0.025
Flurandrenolide Cream, ointment 0.05
Fluticasone propionate Cream 0.05
Fluticasone propionate Ointment 0.005
Mometasone uroate Cream 0.1
Triamcinolone acetonide Cream, ointment 0.1
Hydrocortisone probutate Cream 0.1
Hydrocortisone valerate Cream, ointment 0.2
Prednicarbate Cream 0.1
Desonide Cream, gel, oam, ointment 0.05
Fluocinolone acetonide Cream, solution 0.01
Hydrocortisone Cream, lotion, ointment, solution 0.25, 0.5, 1
Hydrocortisone acetate Cream, ointment 0.5–1
Monitoring
Consider monitoring:
Fasting glucose levels, blood pressure lipids, weight,
height/weight or children, DEXA scans (T score , –2.5
5 osteoporosis), MRI i pain in hip/shoulder/knee
(osteonecrosis), and slit-lamp examination q6–
12 months
Screening or inectious disease (TB, hepatitis, HIV)
Tests to evaluate adrenal insufciency
■
AM cortisol: primary screening tool, .10 mcg/dL 5
good basal adrenal unction
■
24-hour urine ree cortisol: more accurate test or
basal adrenal unction (advantage); main disadvantage
is patient compliance with 24-hour urine collection
■
ACTH stimulation: most commonly used provocative
test or adrenal unction; check basal cortisol level →
Ointment 0.05
Cream 0.05
45
CHAPTER 2 Dermatopharmacology
then inject ACTH → check cortisol levels at 30 and
60 minutes
■
Others: insulin hypoglycemia, metyrapone, and CRH
2.4 IMMUNOMODULATORY AGENTS
Apremilast and other PDE-4 inhibitors
Intracellular phosphodiesterase-4 (PDE-4) inhibitor
■
PDE-4 hydrolyzes cAMP (an intracellular messenger
which regulates inammation) to AMP
■
Inhibiting PDE-4 → ↑ cAMP → ↓ IFN-g, TNF-a, IL-23,
and ↑ IL-10 (anti-inammatory mediator)
Food and Drug Administration (FDA) approved or
psoriasis, psoriatic arthritis, and Behçet’s disease
AEs: diarrhea, nausea, weight loss, depression (1%)
Dose halved in patients with severe renal impairment
■
No reports o TB or malignancy
Crisaborole (FDA approved or atopic dermatitis in
patients aged 31 months) and roumilast (FDA
approved or psoriasis in patients aged 121 years) are
topical PDE-4 inhibitors
■
Crisaborole AEs: application site pain (burning,
stinging); roumilast AEs (diarrhea, headache)
Janus Kinase (JAK) and Tyro inhibitors
Mechanism o action
Regulates intracellular signaling via the JAK STAT pathway
(Fig. 2.1); inhibits gene transcription/growth actor
signaling pathways and cytokine production
There are 4 JAK proteins (JAK1-3, TYK2) and 7 STAT proteins
(STAT1-4, 5A, 5B, 6)
Agents used in dermatology
Toacitinib: JAK 1 and 3 inhibitor; FDA approved or
rheumatoid arthritis and psoriatic arthritis
Ruxolitinib: JAK 1 and 2 inhibitor; 1.5% cream FDA
approved or atopic dermatitis and non-segmental vitiligo;
max o 60 g/wk, tx area , 20% BSA or atopic dermatitis
and , 10% or vitiligo
Upadacitinib: JAK 1 inhibitor; FDA approved or moderate to
severe atopic dermatitis [12 years and older], psoriatic
arthritis and rheumatoid arthritis
Abrocitinib: JAK 1 inhibitor; FDA approved or moderate
to severe atopic dermatitis in adults
Baricitinib: JAK 1 and 2 inhibitor; FDA approved or
severe alopecia areata and rheumatoid arthritis in adults
Deucravactinib: TYK2 inhibitor; FDA approved or
moderate to severe psoriasis in adults
Fig. 2.1 Upon cytokine binding to their receptors, Janus kinase (JAK) amily members are recruited and activated through tyrosine-phosphorylation o their cytoplasmic
domains, which results in phosphorylation o signal transducer and activator o transcription (STAT). STAT heterodimers and homodimers translocate to the nucleus
and bind to DNA sequencesat the promoter regions o genes that regulate cell prolieration, dierentiation, and apoptosis. (From Canesin G, Krzyzanowska A, Hellsten
R, Bjartell A. Cytokines and Janus kinase/signal transducer and activator o transcription signaling in prostate cancer: overview and therapeutic opportunities. Curr
Opin Endocr Metab Res. 2020;10:36-42.)
46
2.4 Immunomodulatory Agents
Adverse eects
Common: upper respiratory inections, diarrhea/nausea,
headaches, increases in cholesterol/LFTs/CPK/Cre, herpes
simplex/zoster, acne
Serious: cardiovascular death/event risk, severe inections
(e.g. TB, invasive ungal inections, viral reactivation),
malignancy (e.g. lymphoprolierative disorders, lung
cancer, non-melanoma skin cancer), thromboembolism
(e.g. DVT, pulmonary embolism, arterial thrombosis), GI
peroration, neutropenia/lymphopenia/anemia
Major adverse cardiovascular death/event and
thromboembolism risk higher in those over 50 years with
at least 1 risk actor
Deucravacitinib does not carry black box warnings like the
other JAK inhibitors; when used appropriately, topical
ruxolitinib appears to be quite sae
Laboratory monitoring
Monitoring depends o specifc medication but includes
TB testing (baseline), hepatitis panel (baseline),
pregnancy testing (baseline; i appropriate), lipid panel,
LFTs, Cr/eGFR, CBC w/ dierential
Azathioprine
Mechanism o action (Fig. 2.2)
Azathioprine’s active metabolite, 6-TG (thioguanine),
is produced by the hypoxanthine guanine
phosphoribosyltranserase (HPRT) pathway and shares
similarities with endogenous purines → incorporated into
DNA and RNA (S-phase o replication) → inhibits purine
metabolism and cell division (particularly in ast-growing
cells that do not have a salvage pathway, like lymphocytes)
Xanthine oxidase and thiopurine methyltranserase
(TPMT) convert azathioprine into inactive metabolites
■
↓ activity o TPMT (measured by allele activity) or
↓ xanthine oxidase (as a result o allopurinol or
ebuxostat) → ↑ azathioprine levels → ↑ risk o liethreatening myelosuppression
■
ACE inhibitors, sulasalazine, and concomitant use o
olate antagonists also increases risk o
myelosuppression
■
Azathioprine may decrease anticoagulant eects o
wararin and reverse neuromuscular blockade
Diminishes T-cell unction . antibody production by B
cells
Adverse eects
Leukopenia (correlates with low TPMT activity)
Cutaneous squamous cell carcinoma (SCC) and
lymphoma (controversial)
Inection (particularly human papilloma virus [HPV],
herpes simplex virus [HSV])
Teratogenicity
Hypersensitivity syndrome: occurs within the frst
4 weeks o therapy; ever, nausea, vomiting, diarrhea,
RAPIDLY CLEAVED NONENZYMATICALLY
BY SULFHYDRYL CONTAINING COMPOUNDS
Genetic
predisposition
Catabolized to
inactive, nontoxic
metabolites
(6-methyl
mercaptopurine)
6-thioguanine (active toxic purine analog that mediates principal drug effect)
TPMT XO
Lesch-Nyhan
syndrome
6-thioinosine 5-monophosphate
AZA
6-MP
HPRT
IMPD
GMPS
Medications
(Allopurinol)
TPMT
lmidazole derivative
(methylnitroimidazole moiety)
mediates some
immunosuppressive effects
Catabolized to
inactive, nontoxic
metabolites
(6-thiouric
acid)
Methylated metabolites
(6-methyl thioinosine
5-monophosphate)
mediate some
immunosuppressive effects
Fig. 2.2 Azathioprine metabolism. 6-MP, 6-Mercaptopurine; AZA, azathioprine; GMPS, Guanosine monophosphate synthetase; HPRT, hypoxanthine guanine phos-
phoribosyltranserase; IMPD , Inosine monophosphate dehydrogenase; TPMT, thiopurine methyltranserase; XO, xanthine oxidase. (Redrawn rom Patel AA, Swerlick
RA, McCall CO. Azathioprine in dermatology: the past, the present, and the uture. J Am Acad Dermatol . 2006;55[3]:369–389.)
47
CHAPTER 2 Dermatopharmacology
arthralgia, and malaise → hypotension, shock; resolves
with discontinuation
■
Skin maniestations may mimic neutrophilic
dermatosis
Gastrointestinal (GI) AEs—most common AEs—nausea,
vomiting, diarrhea, gastritis, and pancreatitis
Hepatoxicity is rare
I given with TNF-a inhibitor → ↑ risk o hepatosplenic
T-cell lymphoma in patients with inammatory bowel
disease
Important monitoring points
TPMT assay beore starting therapy (homozygous TPMT
defciency is a contraindication to therapy)
Monitor CBC, comprehensive metabolic panel (CMP;
with LFTs) every 2 weeks or 2 months, then every
2–3 months
Skin exams due to SCC and lymphoma risk
Cyclosporine
Mechanism o action
Forms a complex with cyclophilin, which inhibits
calcineurin—an intracellular enzyme—which in turn
reduces the activity o nuclear actor o activated T cells/
NFAT-1(transcribes various cytokines, such as IL-2)
↓ IL-2 production → ↓ CD4 and CD8 T-cell activation
Important pharmacology points
Rapid onset o action; cyclosporine should ideally be
gradually tapered while an alternative therapy is instituted
to prevent aring
Microemulsion ormulation more easily absorbed
Maximum dermatologic dose 5 5 mg/kg daily and can
be used continuously or up to 1 year according to the
FDA (2 years or worldwide consensus data)
■
Microemulsion ormulation maximum dermatologic
dose 5 4 mg/kg
Bioavailability determined by CYP450
↑ risk o nonmelanoma skin cancer (NMSC) in psoriasis
patients, especially those who have history o psoralen
plus ultraviolet light A (PUVA)
■
Risk o other malignancies, such as lymphoma, is unclear
Hyperlipidemia not uncommon—dietary changes and
↑ physical activity should be recommended
↑ risk o myopathy when taken with statins
Other AEs include: hypertrichosis, gingival hyperplasia,
myalgia, neurologic AEs (paresthesia, tremors), malaise,
hyperuricemia (can precipitate gout), hypomagnesemia,
and hyperkalemia
Important monitoring points
Recheck creatinine level i ↑ by . 30% rom baseline on
two separate readings 2 weeks apart → i remains elevated
above 30%, ↓ dose by at least 1 mg/kg or 4 weeks, then:
■
I the creatinine level drops back down to , 30%
above baseline, can continue therapy
■
I the creatinine level remains elevated, then
discontinue therapy; i it returns to within 10% o
baseline, cyclosporine can be resumed at a lower dose
■
I at any time the creatinine level increases by $ 50%
above baseline, discontinue therapy until the level
returns to baseline
Blood pressure, blood urea nitrogen (BUN), and
creatinine levels should be measured at baseline, weeks 2,
4, 6, and 8, and then monthly
Baseline CBC, CMP (including uric acid, Mg
urinalysis (UA), lipid profle—recheck monthly
11
, K1),
Regular dental care
No risk o teratogenicity in pregnancy
Methotrexate
Mechanism o action
Binds dihydroolate reductase with greater afnity than
olic acid → prevents conversion o dihydroolate to
tetrahydroolate (a necessary coactor o purine synthesis)
→ inhibition o cell division (S phase specifc)
Indications
FDA approved or psoriasis but used o-label or various
inammatory and autoimmune dermatoses
Adverse eects
Contraindicated in patients with uncontrolled HTN, renal
disease, serious inections, and in those with a previous
history o malignancy
Nephrotoxicity and HTN are the two most notable AEs,
which are dose- and duration-dependent
■
2° to vascular dysunction (renal vasoconstriction) and
tubular dysunction
■
Irreversible kidney damage is avoided i patients receive
dermatologic doses (2.5–5 mg/kg daily), have dose
adjusted when creatinine increases by 30% rom
baseline, and use cyclosporine or no longer than 1 year
■
HTN can be managed by medication rather than by
dose reduction
Prescription o choice 5 calcium channel blockers
(CCBs; e.g., niedipine or isradipine)—vasodilate renal
arterioles and do not alter cyclosporine serum levels
48
Important pharmacology points
The inhibition o dihydroolate reductase may be
bypassed by leucovorin (olinic acid) or thymidine
■
Folinic acid: naturally occurring olate (vitamin B9)
used or rescue o high-dose MTX AEs (pancytopenia)
Folic acid (synthetic) and olinic acid (naturally
occurring): ↓ MTX-induced AEs
■
↓ GI AEs by 26% (nausea, vomiting, and abdominal pain)
■
↓ risk o LFT abnormalities by 76%
■
↓ risk o pancytopenia
■
↑ ability to tolerate MTX (↓ MTX discontinuation rate
or any reason)
Folic acid supplementation likely has minimal impact on
MTX efcacy
MTX-induced hepatic fbrosis—liver biopsy is gold
standard
■
Risk actors (signifcant alcohol consumption,
abnormal LFTs, hepatitis, genetic liver disease, diabetes
mellitus [DM], obesity, hyperlipidemia, exposure to
hepatotoxins)—liver biopsy indicated ater 1 to 1.5 g
o MTX
2.4 Immunomodulatory Agents
■
American College o Rheumatology guidelines: no risk
actors—liver biopsy indicated when:
5/9 LFTs elevated in a 12-month period (LFTs
checked q3–4 months)
3.5 to 4.0 g total cumulative dosage
■
Other tests or liver toxicity: magnetic resonance
elastography, vibration-controlled transient elastography,
algorithm-based serologic testing, and the amino
terminus o type III procollagen peptide assay (PIIIP)
Indications and contraindications
FDA approved or psoriasis and mycosis ungoides (MF)
O-label dermatologic uses include: pemphigus,
pemphigoid, autoimmune connective tissue diseases,
sarcoidosis, vasculitis, and other inammatory dermatoses
Absolute contraindications: pregnancy (teratogenic,
abortiacient), alcoholism, immunodefciency syndromes,
chronic liver disease, severe hematologic abnormalities,
and lactation
■
Contraception required ater completion: 3 months
(M), one ovulatory cycle (F)
Relative contraindications: ↓ renal unction, hepatic
disease, metabolic disease (i.e., obesity or DM),
childbearing age, active inectious disease or history o
potentially serious inection that could reactivate, and
malignancy
Important monitoring points
Viral hepatitis panel and TB at baseline; CBC w/
dierential, LFTs, BUN/creatinine at baseline, then monthly
or several months, decreasing requency to q3–4 months
May repeat CBC ater 1 week to check or bone marrow
suppression
Mycophenolate moetil
Mechanism o action
Binds and inhibits inosine monophosphate
dehydrogenase—a key enzyme or the de novo synthesis
o purines—which is essential in activated lymphocytes
which cannot use purine salvage
Important pharmacology points
Requires gastric acidity or cleavage into its active state
(antacids and proton pump inhibitors ↓ serum levels)
Dermatologic doses range rom 2 to 3 g divided in twice-
daily doses
Indications
FDA approved or renal, cardiac, and liver allograt
rejection prevention, but used o-label in various
autoimmune and inammatory dermatoses (e.g., atopic
dermatitis, pemphigus, lupus, etc.)
Adverse eects
Rarely reported to cause acute pneumonitis, which is
idiosyncratic and can be lie-threatening i MTX is not
stopped, and pulmonary fbrosis (even less common)
■
Routine radiography or pulmonary unction studies,
without symptoms to suggest pneumonitis, are not
helpul in preventing lung toxicity
Pancytopenia, which can be lie-threatening, usually
occurs early (initial 4–6 weeks) in therapy and may be
idiosyncratic
■
Risk actors: old age, poor renal unction, and lack o
olic acid supplementation
No data that patients with psoriasis and taking MTX have
↑risk o malignancy such as lymphoma
GI AEs are common (nausea/anorexia . diarrhea,
vomiting, and ulcerative stomatitis)
MTX has been reported to accumulate in renal tubules
and cause renal toxicity when given at high doses or
chemotherapy
Increased serum levels due to decreased renal unction can
result in skin necrosis, including epidermal necrosis
limited to psoriatic plaques
Other AEs: alopecia, headaches, atigue, dizziness,
accelerated nodule development in patients with
rheumatoid arthritis (RA; similar to rheumatoid
nodules, but smaller and classically on fngers) and
phototoxicity (including UV and radiation “recall
reactions”)
↑ risk o myelosuppression when co-administered with
agents that inhibit olic acid metabolism (e.g.,
trimethoprim, sulonamides, and dapsone) or increase
MTX levels by displacing MTX rom bound plasma
proteins (tetracyclines, phenytoin, phenothiazines,
sulonamides, NSAIDs, and salicylates)
Adverse eects
Absolute contraindications: pregnancy (teratogen) and
drug allergy
Relative contraindications: lactation (may be excreted in
breast milk), peptic ulcer disease, hepatic or renal disease
(may require dose adjustment), drugs that interere with
enterohepatic circulation (e.g., cholestyramine), and
concomitant administration with azathioprine (↑ risk o
bone marrow toxicity)
Risk o carcinogenesis (lymphoma and
lymphoprolierative malignancies) shown in transplant
population (who usually had several immunosuppressive
medications given concomitantly)—unknown whether
this holds true in dermatologic patients and whether there
is increased risk o NMSC
Most common AEs 5 diarrhea, abdominal pain, nausea,
and vomiting
Associated with a orm o neutrophil dysplasia termed
pseudo-Pelger- Huët anomaly, which is characterized by
nuclear hypolobulation with a let shit—this may predict
the development o neutropenia
Monitoring guidelines
CBC/dierential, CMP (w/ LFTs) at baseline, then q2–
4 weeks ater initiating treatment or dose escalation, and
then q2–3 months once the dose is stable
Baseline hepatitis B and C panel, TB screen
Cytotoxic agents
Hydroxyurea
Impairs DNA synthesis through inhibition o
ribonucleotide diphosphate reductase; hypomethylates
DNA resulting in altered gene expression
49
CHAPTER 2 Dermatopharmacology
FDA approved or SCC o head and neck
Dermatologic uses are mainly o-label or treatment o
polycythemia vera, Sweet’s syndrome, erythromelalgia,
and hypereosinophilic syndrome
Severe anemia, thrombocytopenia, and leukopenia are
relative contraindications
Most common AE: megaloblastic anemia
(myelosuppression)
Can cause dermatomyositis-like eruption, lichenoid drug
eruption resembling GVHD, leg ulcers, alopecia,
photosensitivity, radiation recall, and hyperpigmentation
o the skin and nails
Cyclophosphamide
An alkylating agent (exerts its eect by directly damaging
DNA via cross-linking)
■
Nitrogen mustard derivative
■
Aldophosphamide, one o its metabolites, is cleaved
intracellularly into acrolein and enhances cellular
damage by depleting glutathione store
FDA approved or the treatment o MF (advanced disease)
O-label dermatologic uses: severe immunobullous
disease (e.g., ocular cicatricial pemphigoid), severe
systemic vasculitides, neutrophilic dermatoses, and
autoimmune connective tissue diseases
Hemorrhagic cystitis occurs in 5%–41% as a result o
acrolein (prevented by adequate hydration as well as
mesna, which binds acrolein in the bladder and reduces
irritation)
■
↑ risk o transitional cell carcinoma o the bladder,
non-Hodgkin’s lymphoma, leukemia, and SCC (in
transplant and oncology patients)
■
Monitoring: periodic urine analysis with cytologic
examination
Nausea and vomiting are the most common AEs and can
be decreased by co-administering with ondansetron and
dexamethasone
↑ risk o inertility: amenorrhea (27%–60%); premature
ovarian ailure (up to 80%)
Cutaneous AEs: permanent pigmented band on the teeth,
anagen euvium, and hyperpigmentation o skin and
nails
Chlorambucil
Alkylating agent that directly damages DNA via cross-
linking
Rare o-label dermatologic uses: necrobiotic
xanthogranuloma (shown to be eective and sae in a
retrospective review o 48 cases), pyoderma gangrenosum,
and immunobullous and connective tissue disease
Allergy to nitrogen mustard is a contraindication
Epileptogenic and mood-altering potential
Other AEs: nausea, vomiting, azoospermia, amenorrhea,
pulmonary fbrosis, hepatotoxicity, bone marrow
suppression, and oral ulcers
Antimalarial agents
Include hydroxychloroquine (HCQ), chloroquine (CQ),
and quinacrine (o the market in the United States, but
still available in compounding pharmacies)
Mechanism o action
Unknown, thought to work via several dierent proposed
mechanisms:
■
Inhibit UV-induced cutaneous reactions by binding to
DNA and inhibiting superoxide production
■
Raise intracytoplasmic pH and stabilize lysosomes → ↓
ability o macrophages to express MHC complex antigens
on cell surace (↓ antigen presentation, inammation)
■
Reduce lysosomal size and impair chemotaxis
■
Block toll-like receptors
■
Inhibit platelet aggregation and adhesion
(antithrombotic)
Important pharmacology points
CQ and HCQ have long hal-lives and steady-state
concentration is attained at 3 to 4 months, which explains the
long treatment duration required to achieve clinical beneft
Quinacrine may be added to HCQ or CQ or
↑ therapeutic eect
CQ and HCQ should not be given together
Indications
FDA approved or lupus, malaria, and RA
O-label dermatologic uses: particularly useul in
disorders with signifcant lymphocytic infltrates
(polymorphous light eruptions, lymphocytic infltrate o
Jessner, lupus panniculitis, and discoid lupus
erythematosus [LE]), GVHD, sarcoid
Low (twice-weekly) dosing used in porphyria cutanea
tarda (PCT)
Adverse eects
Possibly sae in pregnancy with debatable risks (CQ . HCQ)
Absolute contraindications: hypersensitivity to the drug
(may have cross-reaction between CQ and HCQ);
continued use is contraindicated in patients who develop
retinopathy
Relative contraindications include severe blood dyscrasias,
signifcant hepatic dysunction, signifcant neurologic
disorders, retinal or visual feld changes, pregnancy and
lactation (however, some suggest that the risk o
discontinuing treatment in pregnancy in patients with SLE
outweighs the risk o toxicity to the etus), and psoriasis
CQ is contraindicated in patients with myasthenia gravis
Mucocutaneous drug reactions:
■
Afnity or melanin (skin and retina)—absorbs UV
light
■
Yellow pigmentation o the skin (quinacrine)
■
Lichenoid drug eruption
■
Morbilliorm hypersensitivity eruption; may also
present as erythroderma or Stevens-Johnsons syndrome
(SJS)
Risk is much greater in dermatomyositis (31%)
than lupus (3%)
■
Psoriasis exacerbation (CQ in particular)
■
Bluish-gray to black hyperpigmentation in 10% to
30% o patients treated or $ 4 months typically
aecting the shins (clinically indistinguishable rom
type II minocycline hyperpigmentation), ace, and
palate
■
Hair hypopigmentation (CQ)
50
■
Nail hyperpigmentation
Ophthalmologic toxicity includes corneal deposits
(keratopathy), neuromuscular eye toxicity (ciliary body
dysunction), and retinopathy (maculopathy)
■
Premaculopathy is reversible, but bull’s eye retinopathy
is irreversible
■
Ocular toxicity is NOT seen in quinacrine therapy
■
Additive risk o retinal toxicity when CQ and HCQ
combined
Current eye monitoring recommendations rom American
Academy o Ophthalmology:
■
Maximum daily dose o HCQ , 5.0 mg/kg real weight
■
Fundus examination within frst year o starting
therapy
■
Annual screening ater 5 years o treatment (some
patients, such as the elderly, may require more requent
examinations)
GI AEs (CQ . HCQ): most common reason or early
reduction or D/C o treatment
Restlessness, excitement, conusion, and seizures (usually
in patients on higher-than-recommended doses)
Rare, but potentially atal, bone marrow toxicity has
been reported with quinacrine and agranulocytosis
with CQ
Hemolysis in the glucose-6-phoshate dehydrogenase
(G6PD)-defcient population is mainly a concern or
8-aminoquinoline and primaquine, but not or usual
doses o HCQ and CQ
■
G6PD testing is not necessary or HCQ, CQ, and
quinacrine given low risk o hemolysis with therapeutic
doses
Dapsone
Mechanism o action
Inhibits myeloperoxidase → ↓ oxidative damage to
normal tissue in various neutrophilic dermatoses (aects
eosinophils and monocytes to a lesser extent)
Also ↓ hydrogen peroxide and hydroxyl radical levels
It may also ↓ chemotaxis o neutrophils, although this has
not been demonstrated in therapeutic doses
Important pharmacology points
Dapsone undergoes signifcant enterohepatic
recirculation, thus remaining in the circulation 30 days
ater a single dose
Hemolysis has been demonstrated in nursing inants o
mothers taking dapsone. No harmul in utero
developmental eects are demonstrated when taken
during pregnancy, but theoretical risk o neonatal
hyperbilirubinemia
There is signifcant variability both in individual rates o
acetylation (not clinically relevant) and hydroxylation.
The hydroxylamine metabolite dapsone hydroxylamine
(DDS-NOH) is responsible or hematologic AEs.
Indications
FDA-approved indications are dermatitis herpetiormis
and leprosy
O-label dermatologic uses are numerous and include
various neutrophilic dermatoses (linear IgA dermatosis,
2.4 Immunomodulatory Agents
bullous SLE, erythema elevatum diutinum, pyoderma
gangrenosum, Sweet’s syndrome, neutrophilic urticaria,
subcorneal pustular dermatosis/IgA pemphigus, and
Behçet’s disease), and vasculitides
■
Most patients treated with dapsone or dermatitis
herpetiormis rapidly respond within 24 to
36 hours
Adverse eects
Cross-reactivity between dapsone and sulapyridine, or
other sulonamide-type drugs, is rare
Greater care should be taken in patients with
increased risk o developing hematologic,
cardiovascular, or pulmonary AEs (patients with G6PD
deiciency; signiicant cardiopulmonary, liver, or renal
disease)
Hemolytic anemia and methemoglobinemia: dose-
related and occurs in ALL individuals to some degree
(related to oxidative stress rom N-hydroxy
metabolites)
■
↑ methemoglobin → ↓ oxygen-carrying capacity →
may exacerbate preexisting cardiopulmonary disease
■
Can cause a alsely low hemoglobin A1c
■
Cimetidine decreases the risk o methemoglobinemia
without aecting dapsone’s plasma level
■
Vitamin E may also provide small amount o
protection against methemoglobinemia
■
Methemoglobinemia emergency → use methylene
blue
■
Worsening o methemoglobinemia has been shown
intra- and postoperatively ater both local amide and
general anesthetic; vitamin C can be used when this
occurs
Agranulocytosis, the most serious idiosyncratic
reaction to dapsone, occurs between 3 and 12 weeks
and may maniest as ever, pharyngitis, and occasionally
sepsis
■
Most recover quickly ater cessation o dapsone; may
consider giving G-CSF
Peripheral neuropathy (predominantly distal motor)
1 some degree o sensory involvement; may present
as wasting o hand muscles; reversible i detected
early
Nausea, gastritis, reversible cholestasis and hepatitis, and
hypersensitivity syndrome (typically ater 3–12 weeks o
therapy) have also been reported
Important monitoring points
Baseline G6PD level (lower levels may preclude patient
rom receiving medication, or require ↓ dose)
CBC w/ dierential, LFTs, renal unction tests, and UA at
baseline
Must monitor CBC very closely during “high-risk
window” or agranulocytosis: CBC weekly or 4 weeks,
then every 2 weeks until 3 months into treatment
(agranulocytosis is most common in frst 12 weeks o
treatment)
Ater 3 months, continue checking renal unction, LFTs,
and UA q3–4 months
Methemoglobin levels are needed i there is clinical
suspicion o decreased oxygen circulation or anemia
51
CHAPTER 2 Dermatopharmacology
Biologics (Fig. 2.3, Table 2.5)
TNF-a inhibitors
Etanercept
Fully human dimeric usion protein (TNF-receptor linked
to Fc portion o IgG) that binds both TNF-a (soluble and
membrane-bound) and TNF-b
Subcutaneous
Iniximab
Chimeric monoclonal IgG antibody binding TNF-a
(targets soluble and transmembrane TNF receptor)
Intravenous
Adalimumab
Fully human monoclonal IgG antibody against
transmembrane TNF receptor
Subcutaneous
Certolizumab pegol
PEGylated TNF-a inhibitor—attachment o PEG polymers
delays metabolism and increases hal-lie
Lacks an IgG Fc region—limits transer through the placenta
and decreases teratogenic potential during pregnancy
Subcutaneous
Golimumab
Human monoclonal IgG antibody against soluble and
transmembrane TNF
Subcutaneous
Indications
FDA approved or plaque psoriasis and psoriatic arthritis;
adalimumab approved or hidradenitis suppurativa
Golimumab approved or psoriatic arthritis but not
psoriasis
Etanercept approved or pediatric psoriasis age . 4
Adalimumab
Infliximab
Ustekinumab
Th1 T-cell
IL-12
Etanercept
Certolizumab
TNFα
Adverse eects
Injection site reactions: etanercept (14%)
. adalimumab (3.2%)
■
For etanercept, these are believed to be most
pronounced during the second injection and usually
improve ater 1 month o therapy (hypothesized to be
caused by delayed-type hypersensitivity). Treatment is
to change to a new injection site
Iniximab commonly causes inusion reactions (20%):
■
Nausea, headache, ushing, dyspnea, injection site
infltration, and taste perversion
■
↓ inusion rate and premedication may help
■
Epinephrine and systemic CS are given or serious
reactions (less than 1% o treated patients) including
hypotension, chest pain, dyspnea, anaphylaxis, and
convulsions
Multiple case series report patients on TNF-inhibitors
developing various demyelinating diseases (e.g., multiple
sclerosis, Guillain-Barré syndrome, and optic neuritis)
Development o psoriasis, palmoplantar pustulosis,
connective tissue disease (1ANA, lupus, DM) and
cutaneous vasculitis have been reported with all TNF
inhibitors
■
Highest risk o drug-induced lupus with iniximab;
treatment is withdrawal o drug
Malignancy risk, particularly lymphoma and possibly skin
cancer, may be increased in patients treated with biologic
agents
■
Hepatosplenic T-cell lymphoma (atal) has been
reported in patients on TNF inhibitor 1 azathioprine
↑ risk o TB (primary inection and reactivation), invasive
ungal inections, and opportunistic inections like
legionella and listeria
■
Contraindicated i patient has active inection
■
Screening test or TB beore starting treatment
Conicting evidence exists as to whether TNF inhibitors
may increase risk o developing or exacerbating CHF →
should be used w/ caution in at-risk population
(particularly iniximab)
Reactivation o hepatitis B
■
TNF inhibitors are thought to be sae in hepatitis C, HIV
Neutralizing anti-drug antibodies usually orm beore
week 24 o treatment and interere with the biologic
agent’s binding activity → ↓ decrease efcacy
■
Studies show that anti-drug antibodies directed against
iniximab (5.4%–43.6%) and adalimumab (6%–45%) →
↓efcacy and serum levels; eect not seen with etanercept
■
Co-administration with MTX may → ↓ rates o
antibody ormation
Activated
Dendritic
Cell
Fig. 2.3 Mechanism o action o biologic drugs or psoriasis. IL, Interleukin;
TNF, tumor necrosis actor
IL-23
Ustekinumab
Guselkumab
Tildrakizumab
Risankizumab
IL-17
Th17 T-cell
Secukinumab
Ixekizumab
Brodalumab
Keratinocyte
52
Ustekinumab
Fully human monoclonal IgG1 antibody directed against
the common p40 subunit o IL-12 and IL-23
■
IL-12: activates TH1; IL-23: activates TH
■
Ustekinumab may work better in patients with
HLA-C*06:02
FDA approved or adults and pediatric patients aged . 6
years with psoriasis and psoriatic arthritis
URIs are the most requently reported AEs; also increased
risk o inections, including TB reactivation, ungal
disease, and viral illnesses
17
2.4 Immunomodulatory Agents
Table 2.5 Mechanism o Action, Ecacy, and Dosing o Agents or Psoriasis
Drug Mechanism o Action Eectiveness at 10–16 weeksaAdministration Dosing
Etanercept
Adalimumab
Inliximab
Certolizumab PEGylated human monoclonal
Secukinumab IL-17A monoclonal antibody PASI 75 - 83
Ixekizumab IL-17A monoclonal antibody PASI 75 - 89
Brodalumab IL17 receptor monoclonal antibody PASI 75 - 89
Ustekinumab IL-12/-23 monoclonal antibody PASI 75 - 79
Guselkumab IL-23 monoclonal antibody PASI 75 - 87
Tildrakizumab IL-23 monoclonal antibody PASI 75 - 63
Risankizumab IL-23 monoclonal antibody PASI 75 - 89
Apremilast PDE-4 inhibitor PASI 75 - 31
Methotrexate Antimetabolite, inhibits
Acitretin Retinoid PASI 75 - 20
Cyclosporine Inhibits IL-2 PASI 75 - 44
Deucravacitinib TYK2 inhibitor PASI 75 - 53
IL, Interleukin; PASI, Psoriasis Area and Severity Index; PDE-4, phosphodiesterase-4; TNF, tumor necrosis actor.
a
Data rom Armstrong AW, Puig L, Joshi A, et al. Comparison o biologics and oral treatments or plaque psoriasis: a meta-analysis. JAMA Dermatol.
2020;156(3):258–269.
TNF-a receptor antagonist
Human monoclonal anti-TNF-a
antibody
Chimeric TNF-a antibody
anti-TNF-a antibody
dihydroolate reductase
PASI 75 - 40
PASI 90 -18
PASI 100 - 4
PASI 75 -70
PASI 90 - 44
PASI 100 - 17
PASI 75 - 80
PASI 90 - 57
PASI 100 - 27
PASI 75 - 71
PASI 90 - 46
PASI 100 - 18
PASI 90 - 61
PASI 100 - 30
PASI 90 - 71
PASI 100 - 40
PASI 90 - 71
PASI 100 - 40
PASI 90 - 44
PASI 100 - 18
PASI 90 - 71
PASI 100 - 39
PASI 90 - 37
PASI 100 - 13
PASI 90 - 71
PASI 100 - 40
PASI 90 - 12
PASI 100 - 2
PASI 75 - 44
PASI 90 - 21
PASI 100 - 5
PASI 90 - 6
PASI 100 - 1
PASI 90 - 20
PASI 100 - 5
PASI 90 - 27
PASI 100 - 10
Subcutaneous 50 mg twice weekly or 12 weeks, then
Subcutaneous 80 mg initial dose, then 40 mg every
Intravenous 5 mg/kg at week 0, 2, and 6, then every
Subcutaneous 400 mg at week 0, 2, and 4, then 200
Subcutaneous 300 mg at week 0, 1, 2, 3, and
Subcutaneous 160 mg at week 0, then 80 mg at week
Subcutaneous 210 mg at week 0, 1, and 2, then every
Subcutaneous
Subcutaneous 100 mg at week 0, week 4, and then
Subcutaneous 100 mg at week 0 and 4, and then
Subcutaneous 150 mg at week 0 and 4, and then
Oral 30 mg PO BID ater 5-day titrating
Oral or subcutaneous
injection
Oral 25–50 mg daily
Oral 2.5–5 mg/kg/day
Oral 6 mg daily
50 mg once weekly
2 weeks, starting 1 week ater initial
dose
8 weeks
mg every other week or 400 mg every
4 weeks
4,ollowed by 300 mg every 4 weeks
2, 4, 6, 8, 10, 12, then 80 mg every
4 weeks
2 weeks
45 mg (#100 kg) or 90 mg (.100 kg) at
week 0 and 4, then every 12 weeks
every 8 weeks
every 12 weeks
every 12 weeks
starter dose
12–15 mg weekly
■
Long-term saety data did not show increased risk o
inection and malignancy (excluding skin cancer)
Two cases o reversible posterior leukoencephalopathy
syndrome reported
IL-23 inhibitors
Guselkumab, risankizumab, and tildrakizumab selectively
bind the p19 subunit o IL-23, preventing its interation
with IL-23 receptor
FDA approved or psoriasis; guselkumab and
risankizumab also approved or psoriatic arthritis
AEs: URI, injection site reaction (lower risk than
TNF-a inhibitors), arthralgia, GI AEs, HSV inections,
tinea
IL-17 inhibitors
Ixekizumab and secukinumab neutralize IL-17A
Brodalumab antagonizes the IL-17 receptor
FDA approved or psoriasis and psoriatic arthritis (except
brodalumab); ixekizumab and secukinumab approved or
pediatric patients aged . 6 years
Most commonly reported AE 5 nasopharyngitis
53
CHAPTER 2 Dermatopharmacology
■
Other common AEs include URI, injection site
reactions, and headache; candidiasis and herpes
inections have also been reported
■
Can worsen inammatory bowel disease
■
Brodalumab associated with suicidality
Spesolimab
Monoclonal IL-36 receptor (IL1RL2/IL1RAP) antibody
FDA approved or generalized pustular psoriasis ares
(administered as single 900 mg IV dose; can repeat one
week later)
AEs: inusion site reactions, inections (e.g. UTI, herpes
simplex, cellulitis), DRESS, Guillain-Barre syndrome
Rituximab
Chimeric IgG monoclonal antibody targeting the B-cell
surace antigen (CD20)
■
Binds B cells but not plasma cells (do not express
CD20)
■
Kills B cells through multiple mechanisms: apoptosis,
activation o the complement cascade, antibodydependent cell-mediated cytotoxicity and antibodydependent phagocytosis
FDA approved or pemphigus vulgaris, granulomatosis
with polyangiitis and microscopic polyangiitis; used olabel or other autoimmune blistering diseases
Depletion o B cells occurs within 2 to 3 weeks o initial
treatment with sustained depletion or an average o
6 months; B-cell numbers return to normal within the
frst year o treatment
Relative contraindication in patients with history o
bronchospasm, hypotension, or angioedema
Common AEs include: inusion reactions (generally mild
and occur with the frst inusion), HTN, nausea, URI,
arthralgia, pyrexia, and pruritus
■
Patients with history o cardiac or pulmonary
conditions should be more closely monitored as they
are susceptible to severe inusion reactions
Serious AEs: hepatitis B virus reactivation, progressive
multiocal leukoencephalopathy, SJS/toxic epidermal
necrolysis (TEN), serious inection, hepatic ailure, and
myelosuppression
IL-1 inhibitors
Canakinumab (human anti-IL-1b mAB), anakinra
(IL-1 receptor antagonist), rilonacept (usion protein
behaving like a soluble decoy receptor binding
IL-1a and IL-1b), and gevokizumab (humanized
anti-IL-1b mAB)
Anakinra is FDA approved or moderate to severe RA that
has ailed other disease-modiying treatments
O-label uses in dermatology: pyoderma gangrenosum,
pyogenic arthritis, pyoderma gangrenosum and acne
(PAPA) syndrome, hidradenitis suppurativa, lamellar
ichthyosis, Sweet’s syndrome, panniculitis, Muckle-Wells
syndrome and other autoinammatory syndromes (e.g.,
Schnitzler syndrome), and synovitis, acne, pustulosis,
hyperostosis, osteitis (SAPHO) syndrome
Risk o TB reactivation appears to be lower in IL-1
inhibitors than in TNF-a agents, although more studies
are needed
Most common AEs are injection site reactions; important
to monitor absolute neutrophil count as neutropenia
can occur
IL-1 inhibitors should not be initiated in patients with
active inections
Omalizumab
Monoclonal anti-IgE antibody → ↓ IgE levels and ↓ IgE
receptors on mast cells and basophils
FDA approved or asthma and chronic idiopathic urticaria
AEs: anaphylaxis, malignancy, and injection site reaction
■
Unmasking o Churg-Strauss syndrome in patients with
underlying eosinophilic disorder
Dupilumab
IL-4 receptor antagonist, blocks signaling rom both IL-4
and IL-13
■
Key mediators o the TH2 pathway
FDA approved or atopic dermatitis or ages $ 6 months
and prurigo nodularis in adults
AEs: conjunctivitis and keratitis, hypersensitivity/
injection site reactions
Lebrikizumab and tralokinumab
Monocolonal anti-IL-13 antibodies
Tralokinumab approved or atopic dermatitis,
lebrikzumab under investigation
Appear to have lower conjunctivitis risk than dupilumab
and better dosing regimens
Nemolizumab
IL-31 receptor antagonist
Eective against itch in atopic dermatitis and prurigo
nodularis, under investigation
2.5 ONCOLOGIC AGENTS IN
DERMATOLOGY (FIG. 2.4)
Vismodegib and sonidegib
Patched (PTCH) tumor suppressor gene is a receptor or
sonic hedgehog; PTCH inhibits smoothened in the
absence o sonic hedgehog
Vismodegib and sonedigib target sonic hedgehog pathway
by inhibiting smoothened → SUFU stays bound to GLI
→ GLI1/2 transcription actors stay inactive → inhibition
o transcription o target genes
■
Ineective in nevoid BCC syndrome (Gorlin) patients
with SUFU gene mutations (5%)
■
Itraconazole also inhibits hedgehog pathway through
smoothed and GLI
Used or metastatic and locally advanced basal cell
carcinoma (BCC), as well as those unamenable to
54